The development of new forms of therapeutics that use macromolecules such as proteins or nucleic acids as therapeutic agents has created a need to develop new and effective approaches of delivering such macromolecules to their appropriate cellular targets. Therapeutics based on either the use of specific polypeptide growth factors or specific genes to replace or supplement absent or defective genes are examples of therapeutics that might require such new delivery systems. Therapeutics involving oligonucleotides that interact with DNA to modulate the expression of a gene or other segment of DNA might also require a new delivery system. Clinical application of such therapies depends not only on the reliability and efficiency of new delivery systems but also on their safety and on the ease with which the technologies underlying these systems can be adapted for large-scale pharmaceutical production, storage, and distribution of the therapeutic formulations.
Gene therapy has become an increasingly important mode of treating various genetic disorders. The potential for providing effective treatments, has stimulated an intense effort to apply this technology to diseases for which there have been no effective treatments. Recent progress in this area has indicated that gene therapy can have a significant impact not only on the treatment of single gene disorders, but also on other more complex diseases such as cancer. However, a significant obstacle in the attainment of efficient gene therapy regime has been the difficulty of designing new and effective approaches for delivering therapeutic nucleic acids to cells and intracellular targets. Indeed, an ideal vehicle for the delivery of nucleic acids or proteins into cells and tissues should be highly efficient, safe to use, easy to produce in large quantity and have sufficient stability to be practicable as a pharmaceutical delivery vehicle.
When nucleic acids are used as “active agents” in a gene therapy regime, there are essentially two systems based on viral vectors or nonviral vectors that are described in the art: (1) retro, adeno and herpes viruses (or their recombinants) are presently being studied in vivo as viral vectors; and (2) liposomes and ligands of cell surface-specific receptors are being researched in vivo as nonviral vectors (Wu & Wu, (1991) Biotherapy 3: 87-95; Ledley, (1993) Clin. Invest. Med. 16: 78-88). Nanocrystalline particles are also being investigated (U.S. Pat. No. 5,460,831 to Kossovsky). All of these approaches suffer from a variety of disadvantages, including undesired in vivo degradation and a lack of specificity for a given target structure, for example, the nucleus of a cell or the surface of a cell expressing a particular type of structure.
Nanoparticle technology has found application in a variety of disciplines, but has found minimal application in pharmacology and drug delivery. The development of therapeutic nanoparticles was first attempted around 1970, and the proposed nanoparticles were intended to function as carriers of anticancer and other drugs (Couvreur et al., (1982) J. Pharm. Sci., 71: 790-92). Attempts were also made to elucidate methods by which the uptake of the nanoparticles by the cells of the reticuloendothelial system (RES) would be minimized (Couvreur et al., (1986) in Polymeric Nanoparticles and Microspheres, (Guiot & Couvreur, eds.), CRC Press, Boca Raton, pp. 27-93). Other attempts pursued the use of nanoparticles for treatment of specific disorders. See, e.g., Labhasetwar et al., (1997) Adv. Drug. Del. Rev., 24: 63-85.
Although nanoparticles have shown promise as useful tools for drug delivery systems, many problems remain. Some unsolved problems relate to the control, selection, and behavior of various particle sizes, as well as problems surrounding the loading of particles with therapeutics. Additionally, the targeting of the nanoparticle to the appropriate cellular site has remained problematic. The design and provision of a nanoparticle delivery vehicle that addresses these problems thus represents and ongoing and long-felt need in the art.